How is Melanoma of the Skin Treated?
Surgery is the mainstay of therapy for early-stage melanoma and for the removal, or resection, of a melanoma. Skin biopsies and sentinel lymph node biopsies (SLNB) are first-line surgical procedures used in diagnosing melanoma; once diagnosed, many other types of surgery are employed when appropriate.
Types of Surgery
The initial biopsy may be performed by a dermatologist or dermatologic surgeon. Surgery to remove melanoma may be performed by a surgical oncologist, a plastic surgeon, a head-and-neck surgeon or by a combination of these specialists, using the following techniques:
- Simple Excision: thin melanomas are removed along with a small amount of non-cancerous skin at the edges.
- Mohs Surgery: a small section of apparently normal skin beyond the visible melanoma is removed and looked at under a microscope. If abnormal cells are identified, another small section is removed and this process continues until the cells removed no longer look abnormal.
- Wide Local Excision: this excision is used to decrease the chance of local recurrence. A wide excision, usually 1-2 cm, is made around the original melanoma site, and the tissue is sent to the pathologist for evaluation under a microscope.
- Sentinel Lymph Node Biopsy: a radioactive tracer and dye are injected into the site of the primary melanoma to “drain” the lymph node basin. They are then examined under a microscope to determine if there are any melanoma cells detected.
Lymph Node Status
Lymph nodes are small glands that work as filters throughout your body. They contain immune cells that help fight infection and destroy germs carried in lymph fluid. There are hundreds of lymph nodes throughout your body and they are located primarily in the neck, armpits and groin.
If the original, or primary, melanoma has certain high-risk characteristics, your doctor may want to examine your lymph nodes. This will help your doctor determine whether melanoma cells have traveled beyond the original site of the lesion. To check this, your doctor will perform a sentinel lymph node biopsy (SLNB). The sentinel node is the first lymph node to which cancer is most likely to spread. If melanoma is found, the surgeon may remove additional lymph nodes to check for melanoma.
The extent of lymph node involvement, as well as other factors, will help your doctor determine your stage of diagnosis. It is very important to find out your stage as this information will help drive your treatment plan. If no melanoma is found in the lymph nodes, then it is likely that no additional surgery will be performed.
Radiation and Chemotherapy
Radiation therapy uses high energy rays, like x-rays, to kill cancer cells. Although radiation is not an overly common melanoma treatment option, it is most often used as a symptom-relieving therapy in patients whose melanoma has spread to the brain or bones. In these situations, the radiation would not be expected to cure the melanoma, but it may help to make the patient more comfortable. Radiation may also be given to high risk Stage III patients after surgery, as a form of adjuvant, or preventative, treatment to reduce the risk of the melanoma spreading or returning.
Radiation treatments only last a few minutes and are much like getting an x-ray, only the radiation is much stronger. Because of the strong energy that is used, radiation therapy requires careful planning to reduce the impact on surrounding, healthy tissues. Be sure to talk to your melanoma treatment team, especially your radiation oncologist, about the pros and cons of radiation for the treatment of melanoma.
Possible side effects of radiation may include:
- Issues to the skin at the site of the radiation
- Loss of appetite
- Weight loss
- Hair loss
Chemotherapy is a medication-based, systemic therapy to treat many types of cancer, including melanoma, by destroying melanoma cells throughout the body. The success of chemotherapy in the treatment of melanoma has been shown to be limited. Chemotherapy is prescribed and administered by a medical oncologist, a physician specially trained in oncology. The medical oncology team usually consists of physicians and specially trained nurses.
- Dacarbazine (DTIC) is the only FDA-approved chemotherapy agent for the treatment of Stage IV melanoma. It is administered as an intravenous infusion.
- Temozolomide is an oral form of dacarbazine. This medication is not FDA-approved for the treatment of melanoma, but is often used in that setting with similar efficacy to its DTIC.
- Other chemotherapy agents are sometimes used for the treatment of metastatic melanoma, including the taxanes (i.e. docetaxel, paclitaxel) and platinum agents (i.e. cisplatin, carboplatin), all with limited success.
Isolated limb perfusion (ILP)
Isolated limb perfusion (ILP) is a technique to deliver chemotherapy to arms or legs without causing overwhelming systemic damage. Roughly half of all melanomas occur in the extremities, and about 10 percent of patients with those lesions develop a recurrence.
Adjuvant therapy in melanoma is a treatment or treatments that are given after primary treatment in order to lower the risk of recurrence (that the cancer may return). Most often in melanoma, the primary treatment is surgery. Surgery aims to remove all visible tumor on physical examination and scans, such as Xrays and CT scans. It is possible that small numbers of cancer cells may be undetectable and therefore not removed by surgery. Adjuvant therapy aims to assist primary treatment by eliminating any microscopic cells that may have escaped surgical removal.
In addition to surgery, radiation is sometimes recommended as an adjuvant treatment if there is a high risk for local occurrence where the tumor or lymph nodes were surgically removed.
Newer, recently approved systemic (traveling through the bloodstream) adjuvant therapies mean that medicines can target cells or enhance the immune system anywhere in the body.
FDA-Approved Adjuvant Treatments for Melanoma
Four immunotherapies and one targeted therapy combination are currently FDA approved for adjuvant therapy of melanoma:
In February 2019, Keytruda was FDA-approved for the adjuvant treatment of patients with melanoma with lymph node(s) involvement, following complete resection. Approval was based on EORTC1325/KEYNOTE-054, a randomized, double-blind, placebo-controlled trial in 1,019 patients with completely resected Stage IIIa, IIIb or IIIc melanoma. The primary efficacy outcome measure was recurrence-free survival (RFS).
Dabrafenib (Tafinlar®) + Trametinib (Mekinist®)
In April 2018, Tafinlar and Mekinist were approved in combination for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection. Approval was based on COMBI-AD (NCT01682083), an international, multi-center, randomized, double-blind, placebo-controlled trial in 870 patients with Stage III melanoma with BRAF V600E or V600K mutations. The major efficacy outcome was relapse-free survival (RFS). Patients who received the combination treatment had a statistically significant improvement in RFS compared with those receiving placebo.
In December 2017, Opdivo was approved as an adjuvant treatment for completely resected Stage III or IV melanoma based on a clinical trial comparing Opdivo to Yervoy. Opdivo is the first PD-1 inhibitor to be approved as an adjuvant therapy in patients with lymph node involvement or metastatic disease who have undergone complete resection. Patients treated with Opdivo had fewer side effects, with 9% of patients discontinuing treatment due to adverse reactions and showed a longer time before a recurrence compared to Yervoy. More time is needed to follow patients and to learn the effect on overall survival.
In October 2015, Yervoy, an anti-CTLA-4 antibody, was approved as an adjuvant therapy in patients with Stage III melanoma based on findings that survival was prolonged when compared to patients treated with placebo. Side effects can be significant, leading to discontinuation of therapy in half of the patients.
Peginterferon alpha 2-b (Sylatron®)
Interferon was approved in 1995 for treatment of high-risk melanoma after surgery. Its use has been controversial due to its harsh side effects and low impact on recurrence and survival. Interferon has not shown a beneficial effect in advanced melanoma.
So, what does this mean for patients?
With new drug approvals, patients have more and better treatment options than ever before. These advances have changed the way patients are treated. Patients with early stage disease completely removed by surgery should discuss adjuvant therapies with their treatment team. Some questions to ask include:
- Will adjuvant therapy decrease my chance of recurrence?
- Which adjuvant therapy do you recommend and why?
- What are the side effects?
- How long would I be treated?
- Is there a clinical trial that would be right for me?
Risk of Recurrence
Adjuvant therapies are recommended for those at moderate or high risk of recurrence. Risk is associated with characteristics of the tumor such as thickness, ulceration, high mitotic (growth) rate and involvement of local lymph nodes. This information is used to determine the stage of melanoma.
Clinical trials are exploring which patients may be at moderate or high risk for recurrence. Trials are also working to determine if there are other factors that can identify which patients would benefit from adjuvant therapy. A medical oncologist will work with a surgeon to determine whether adjuvant treatment may be helpful in lowering the risk of recurrence.
Great progress has been made but questions remain. Clinical trials are testing additional treatments, including vaccines, combination immunotherapies and targeted therapies. Clinical trials are examining the best dose, the duration of treatment, drug combinations vs single drugs, and biomarkers that may help doctors choose the best drug for each patient.
Building on the improvement seen in patients with advanced disease, clinical trials have assessed whether patients with early stage melanoma at moderate to high-risk of recurrence would also benefit. Two immunotherapies already approved for metastatic disease (ipilimumab and nivolumab) are now approved for adjuvant therapy with benefit seen in both BRAF mutant and BRAF wild-type patients. Single agent BRAF inhibitor, vemurafenib, did not show overall benefit as adjuvant therapy. However, results of the combination of a BRAF plus MEK inhibitor trial (dabrafenib plus trametinib) compared to placebo is showing a lot of promise and is being reviewed by the FDA.
The bottom line? Both FDA approved therapies and clinical trials can be a good option for patients. All options should be thoroughly discussed with your treatment team.
Content reviewed by Douglas Johnson, MD
Immunotherapy is a type of systemic (whole body) therapy used for treating metastatic melanoma or melanoma that has a high risk for recurrence (returning). Immunotherapy treats the whole body by attempting to activate a person’s immune system so that it will destroy any melanoma cells within the body.
Immunotherapy is prescribed and administered by a medical oncologist in a variety of ways, most commonly by using biologic agents that stimulate the immune system. Other mechanisms are currently under investigation in clinical trials and include vaccine therapy, intra-lesional therapy, stem cell manipulation and others.
FDA-Approved Immunotherapy Treatments for Melanoma
Commonly prescribed immune stimulants include biologic agents such as antibodies, interferons and interleukins, which are administered in much higher doses than are usually present in the body.
FDA-approved in October 2015. Imlygic is a genetically modified oncolytic viral therapy indicated for the local treatment of unresectable cutaneous, subcutaneous and nodal lesions in patients whose melanoma has recurred after initial surgery. Imlygic is a genetically modified herpes simplex virus type 1 designed to replicate within tumors, causing tumors to rupture (cell death).
Learn more by viewing the Intralesional Therapies in Melanoma webinar:View the webinar!
Ipi + Nivo (Yervoy® + Opdivo®)
Combination was FDA-approved in September 2015 based on improved response rates and progression-free survival in previously treated patients.
FDA-approved in November 2015 as a first line therapy in previously untreated patients who do not have a positive BRAF V600 mutation. It was previously approved in 2014 for patients whose melanoma had progressed following ipilimumab and, if BRAF V600 mutation positive, also a BRAF inhibitor. It is the second anti-PD-1 drug approved for the treatment of unresectable (cannot be removed by surgery) or advanced (metastatic) melanoma, but the only anti-PD-1 therapy approved as a single agent for first-line use in patients with advanced BRAF V600 wild-type (not mutated) melanoma. In December 2017, Opdivo was approved (the first PD-1 inhibitor) as an adjuvant therapy in patients with lymph node involvement or metastatic disease who have undergone complete resection. This includes both BRAF mutant and BRAF wild-type patients. Opdivo is the first and only agent approved for the adjuvant treatment of melanoma based on head-to-head trial against an active comparator (Yervoy) with a proven overall survival benefit.
FDA-approved in 2014 for demonstrating durable responses in patients whose disease has progressed following ipilimumab and, if BRAF V600 mutation positive, also a BRAF inhibitor. Randomized trials are in progress to assess the ability of pembrolizumab to improve time to progression and overall survival. Keytruda is the first anti-PD-1 drug to be approved by the FDA for melanoma.
FDA-approved 2011; the first drug in 13 years to be approved for the treatment of metastatic melanoma. In October 2015, Yervoy was approved as adjuvant therapy in patients with Stage III melanoma.
Peginterferon alpha 2-b (Sylatron®)
FDA-approved in 1995; approved for patients with metastatic melanoma that has been surgically resected and that are at high risk for recurrence (i.e., for adjuvant therapy). Analyses of randomized trials of interferon used in an adjuvant setting show that it can lengthen the time of melanoma recurrence, but it does not appear to prolong survival.
Interleukin-2 (IL-2; Proleukin®)
FDA-approved in 1998; the first drug to be approved for metastatic melanoma; was approved on the basis of long-lasting complete response. Randomized trials of IL-2 have not been conducted, so precise information on long-term overall survival is not available.
Side Effects of Immunotherapy Treatments
Take a look at our Immunotherapy: Managing Side Effects webinar, hosted by Mike Postow, MD of Memorial Sloan Kettering Cancer Center.View the webinar!
Side effects of immunotherapy treatments are not the same as side effects of traditional cancer treatments, like chemotherapy. Side effects are not an indicator that the drug is working or not working. It is very important to report all side effects to your treatment team as soon as you notice them. Most side effects can be managed if they are treated early, and this may allow you to stay on the treatment longer. Because immunotherapies are still relatively new, little is known about the long-term side effects of these treatments. The most common side effects of immunotherapies include:
- Muscle or joint pain
- Itching or rashes
- Colitis or other GI problems
Targeted therapy is a form of treatment in which drugs (or other substances) are developed with the goal of destroying cancer cells while leaving normal cells intact. These drugs are designed to interfere with the specific molecules that are driving the growth and spread of the tumor. Because they are “targeted” to the tumor, these therapies may be more effective and associated with fewer side effects compared to chemotherapy and radiation therapy. A targeted therapy approach allows the classification of melanoma into different “subtypes” based on the genetic profile of the tumor. This facilitates personalized treatment as patients receive drugs based on the unique genetic profile, or subtype, of their tumor. Targeted therapies are usually taken in pills or capsules.
Up-to-date recordings on a variety of melanoma treatments can be found on our Educational Recordings page.
FDA-Approved Targeted Therapies for MelanomaWEBINAR: WHY TEST FOR BRAF?
Encorafenib (Braftovi™) + Binimetinib (Mektovi®)
FDA-approved in June 2018 for the treatment of unresectable or metastatic melanoma with a BRAF V600E or BRAF V600K mutation. The approval followed a phase 3 trial which showed the combination doubled median progression-free survival (mPFS) compared to vemurafenib as a single therapy. It is not indicated for the treatment of patients with wild-type BRAF melanoma.
Vemurafenib (Zelboraf®) + Cobimetinib (Cotellic®)
FDA-approved in November 2015 for the treatment of BRAF V600 mutant melanoma. Vemurafenib was previously approved in 2011 but in research studies, this combination showed improved progression-free and overall survival compared to vemurafenib alone.
Dabrafenib (Tafinlar®) + Trametinib (Mekinist®)
FDA-approved in 2014 for demonstrating durable responses in patients with unresectable or metastatic melanomas that carry the BRAF V600E or V600K mutation. Randomized trials are in progress to assess the ability of the combination to improve time to progression and overall survival compared with dabrafenib alone. Most recently, in April 2018, Tafinlar and Mekinist were approved in combination for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection. Approval was based on an international, multi-center, randomized, double-blind, placebo-controlled trial in 870 patients with Stage III melanoma with BRAF V600E or V600K mutations. The major efficacy outcome was relapse-free survival (RFS). Patients who received the combination treatment had a statistically significant improvement in RFS compared with those receiving placebo.
FDA-approved in 2013 for the treatment of BRAF V600 mutant melanoma that cannot be removed by surgery. This drug is only approved for those patients who have tested positive for the BRAF mutation. It is not indicated for the treatment of patients with wild-type BRAF mutation.
FDA-approved in 2013 for the treatment of BRAF V600E or V600K mutations. It is a first-in-class MEK inhibitor approved for the treatment of unresectable or metastatic melanoma. It is not indicated for the treatment of patients who have received a prior BRAF inhibitor therapy.
FDA-approved in 2011 for the treatment of BRAF V600E mutant melanoma that cannot be removed by surgery. This drug is only approved for those patients who have tested positive for the BRAF mutation.
Genomics and Biomarkers
What is Personalized Medicine?
As research has become more advanced, scientists have discovered that not all types of melanoma are identical. Each cancer is as unique as the patient in which it is found. According to the NCI, personalized medicine, also known as precision medicine, is a “form of medicine that uses information about a person’s genes, proteins, and environment to prevent, diagnose, and treat disease. In cancer, personalized medicine uses specific information about a person’s tumor to help diagnose, plan treatment, find out how well treatment is working, or make a prognosis”.
The MRF’s webinar, Precision Medicine in Melanoma, may help you better understand the importance of genomic testing, biomarkers and what it means for the treatment of melanoma.View the webinar!
Side Effects of Targeted Therapies
Side effects of targeted therapies are not the same as side effects of traditional cancer treatments, like chemotherapy. Side effects are not an indicator that the drug is working or not working. It is very important to report all side effects to your treatment team as soon as you notice them. Most side effects can be managed if they are treated early, and this may allow you to stay on the treatment longer. Because targeted therapies are still relatively new, little is known about the long-term side effects of these treatments. The most common side effects of targeted therapies include:
- Sensitivity to sun
- Development of squamous cell skin cancers
- Joint pain